Following the Age-Related Eye Disease Study (AREDS), a supplement shown to reduce the risk of progression from intermediate to late age-related macular degeneration (AMD) by 25% during a 5-year period was launched. But an ingredient that, in 2001, demonstrated a protective effect — beta carotene — was found to nearly double risk for lung cancer, mostly in patients who formerly smoked. 

In 2013, the Age-Related Eye Disease Study 2 (AREDS2) evaluated ω-3 fatty acids and lutein with zeaxanthin as possible additions to the formulation. Now, after 10 years, a follow-up analysis demonstrates lutein’s benefit continued without raising the risk for lung cancer, offering assurance for clinicians, as published in JAMA Ophthalmology.

In AREDS2, a 5-year clinical trial, patients with intermediate AMD or late AMD in 1 eye were randomized to 4 treatment groups: lutein/zeaxanthin, ω-3 fatty acids, both lutein and ω-3, or placebo. A secondary analysis included patients who never smoked or those who quit smoking at least 1 year prior, randomized to receive either no beta carotene, or beta carotene along with low- or high-dose zinc. After AREDS2, the current 5-year telephone study enrolled existing participants who were mailed the new formulation with 10 mg lutein/2 mg zeaxanthin, vitamin C, vitamin E, copper, and zinc. This epidemiologic follow-up, from December 1, 2012 to December 31, 2018 comprises data on self-reported late AMD or lung cancer diagnosis, in many cases validated by medical records. 


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Investigators conducted statistical analysis between November 2019 and March 2022. Of 4203 individuals in AREDS2, 3882 volunteered to take the reformulated supplements and receive telephone calls spaced 6 months apart. Participants were, on average, 72.0±7.7 years of age at baseline. Also, 673 of those receiving phone checks, plus 36 who were not called were offered in-clinic examinations near the conclusion of this follow-up.

In 10 years, 117 patients developed lung cancer. The odds ratio to contract lung cancer was 1.82 for those who had been randomized to beta carotene (95% CI, 1.06–3.12; P =.02). Most cases of lung cancer involved former smokers. In contrast, the odds ratio was significantly lower, 1.15, for individuals randomized to lutein/zeaxanthin (95% CI, 0.79–1.66; P =.46).

Of 6351 eyes, 3040 progressed to late AMD. Researchers used Kaplan-Meier probability to calculate advancement of disease in patients using lutein/zeaxanthin was 47.9% compared with 49.0% for those not taking this antioxidant. “The hazard ratio (HR) for progression to late AMD comparing lutein/zeaxanthin with no lutein/zeaxanthin was 0.91 (95% CI, 0.84–0.99; P =.02) and comparing ω-3 fatty acids with no ω-3 fatty acids was 1.01 (95% CI, 0.93–1.09; P =.91),” the analysis explains. The hazard ratio for progressing to late-stage AMD was also favorable for the lutein/zeaxanthin-only cohort compared with individuals taking beta carotene only (P =.02).

In addition to the post hoc design, a lack of ophthalmic images for all during this study was a limitation, because investigators could not determine long-term correlations between AREDS2 supplements and two individual AMD subtypes. Also, this sample was mostly well-educated and nourished, so results may not be generalizable. Conversely, a strong participation rate generated robust data. After 7.5 years, more than 1% were still using AREDS supplements, and 91% continued taking AREDS2 formulation.

Disclosure: This research was partially supported by Bausch + Lomb Corporation. Please see the original reference for a full list of disclosures.

Reference

Chew EY, Clemons TE, Agrón E, et al. Long-term outcomes of adding lutein/zeaxanthin and ω-3 fatty acids to the AREDS supplements on age-related macular degeneration progressionJAMA Ophthalmol. Published online June 2, 2022. doi:10.1001/jamaophthalmol.2022.1640